Abstract: Minimally invasive histotripsy systems and methods are provided. In some embodiments, a minimally invasive histotripsy device is inserted into a patient. The device can be inserted endoscopically through a natural orifice of the patient, or laparoscopically through an incision in the patient's skin. The minimally invasive histotripsy device can be advanced to the target tissue and acoustically coupled to the target tissue before applying histotripsy therapy to the target tissue. In some embodiments, the minimally invasive histotripsy device includes a transducer array with a focal length of approximately 10-40 mm, a diameter of less than 35 mm, and the ability to create a peak negative focal pressure of at least 20 MPa.